Identification of risks for licit and illicit substance use in early adolescence is critical for informed design and implementation of substance abuse prevention and interventions. This resubmission of a K01 application is motivated by analyses indicating that offspring of parents with a history of Substance Use Disorder (SUD) who are 'separated' (divorced, or never-married and not cohabiting) are at especially high risk for alcohol, tobacco, marijuana, and other drug use by age 14, and particularly by age 12. The first goal is to conduct a program of secondary data analyses, using both national probability sample (NESARC) and informative twin family datasets, to examine the impact of parental SUD on risk for parental separation, and the consequences of parental SUD, alone and in conjunction with parental separation, for offspring very early licit and illicit substance use, to identify important mediators of observed associations, as well as risk moderators, using genetically-informed methodology. The second goal is to collect pilot data from families with young adolescent offspring (ages 11-13), already ascertained on the basis of birth, marriage, and divorce records, where the biological parents are confirmed at screening interview to be (i) continuously married (N=50); (ii) married at childbirth but subsequently divorced (N=50); (iii) never-married and not cohabiting (N=50), with 50% of families selected, on the basis of the screening and diagnostic interviews, for parental SUD. Telephone diagnostic interviews with mothers and offspring will characterize substance use histories and pertinent psychiatric and sociodemographic risk-factors, and will include concurrent assessment of environmental risk-exposures and measured genes (DMA collection from saliva), creating (in combination with secondary analyses) a foundation for a larger-scale R01-funded prospective study focused on GxE effects associated with parental separation. The proposed combination of secondary data analysis and new pilot data collection, together with a training plan that includes formal and informal didactics and mentoring in areas where the applicant lacks expertise, offers unique opportunities for advanced training in sample ascertainment and data-collection, statistical analysis of epidemiological and molecular genetic data, and grant writing and publication - skills key to the candidate's development as an independent R01-funded research scientist.